Composition and methods for inhibiting the progression macular degeneration and promoting healthy vision

ABSTRACT

The present invention provides improved dietary supplements and methods for inhibiting the progression of macular degeneration and promoting healthy vision. The dietary supplements of the invention contain cobeadlets comprising vitamin E and carotenoids in the form of Vitamin A, lutein and/or zeaxanthing. The dietary supplements of the invention further contain Vitamin C, copper and zinc and may also contain such ingredients as rosemary, DHA, other vitamins and minerals.

Priority is claimed from the provisional application, U.S. patentapplication Ser. No. 60/531,471 filed Dec. 19, 2003.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention generally relates to methods and compositions toalleviate eye diseases and, more specifically, to improved methods andcompositions for the treatment of cataracts and macular degeneration.

2. Description of the Related Art

Macular degeneration associated with aging and drusen is an extremelysignificant concern, and is now a major cause of blindness in the UnitedStates for individuals over 65 years of age. Just at the period of timewhen the eyes are a most important sense, and reading and watchingtelevision are often the most enjoyable avenues of entertainment, thisdisease robs the elderly patient of such possibilities.

The crystalline lens of the eye has only one disease state that we areaware of, and that is cataract. The lens loses its clarity as it becomesopacified, and vision is disturbed depending on the degree ofopacification. There are different etiologies for cataracts such as acongenital lesion or trauma, which are well recognized. It is also knownthat some medicines such as cortisone-type preparations and glaucomamedications can cause cataracts, as can inborn metabolic errors such asgalactosemia. These, however, are relatively uncommon in comparison tothe common aging cataract, which shows an increase in frequency directlycorrelated with age.

The exact incidence of cataracts in the general population is difficultto determine because it depends on one's definition of a cataract. Ifdefined as simply a lens opacity, then obviously the incidence is muchhigher than when defined as a lens opacity that significantly impactsvision. The pathogenesis of age-related cataracts and maculardegeneration is incompletely understood.

The accumulation of drusen and lipofuscin and the loss of retinalpigment, hallmarks of macular degeneration, appear to be a consequenceof the accumulation of biomolecular derivatives of those bioactivemolecules involved in photoreception and signal processing, and normallydetoxified, processed, and exported from the RPE (retinal pigmentepithelium). While the importance of controlling the accumulation oflipofuscin and its dominant component A₂E,N-retinylidene-N-retinylethanolamine (Sparrow, 2001), which isresponsible for converts visible-wavelength radiation into toxic ROSs(reactive oxygen species), no means for accomplishing this has beenproposed and so the best means currently available for limiting thedamage is by reducing the amount of radiation available to thelipofuscin. There also is no effective treatment to date for theresulting biodegeneration, except laser photocoagulation in patients whodevelop abnormal vessels under the retina, i.e., subretinalneovascularization. The treatable group is a distinct minority of a muchlarger group. Individuals so afflicted can anticipate either aprogressive deterioration or at times relatively static course, but nospontaneous improvement, since the basic architecture of the retina isdestroyed. Occasionally, there may be variations in vision which seem toshow improvement depending on such things as lighting in the room andpotential resolution of fluid underneath the retina. The importantpoint, however, is that when this sensitive neurological tissue isdamaged, that damage is permanent.

In 1981, Spector et al. stated that there still remained questionsconcerning the mechanism and agents involved with massive oxidation ofthe lens tissue and its relationship to cataract development (Spector etal. 1981). They also noted that glutathione (GSH) can act as a reducingagent and free radical trapper. Glutathione peroxidase (GSHPX) andcatalase are present to metabolize H₂O₂. While superoxide dismutase(SOD) can detoxify O₂, light can photochemically induce oxidation.However, Spector et al. believe that the actual roles of light and/ormetabolically-generated oxidized components are unclear as to causingthe observed oxidation products.

In 1987, Machlin et al. reported that there was some evidence that freeradical damage contributed to the etiology of some diseases, includingcataract (Machlin et al. 1987). They indicated that defenses againstsuch free radical damage included Vitamin E, Vitamin C, beta carotene,zinc, iron, copper, manganese, and selenium.

In 1988, Jacques et al. reported that it is commonly believed thatoxidative mechanisms are causally linked to, not simply associated with,cataract formation. According to Jacques et al. evidence suggests thatGSHPx and SOD decrease with increasing degree of cataract.

Jacques et al. further reported that Vitamin E is believed to be adeterminant of cataract formation and can act synergistically with GSHPxto prevent oxidative damage. They point out the possibility that VitaminC may have a role in cataract formation and might influence GSHPxthrough its ability to regenerate Vitamin E.

Dietary supplements are taken for a variety of reasons including theimprovement of vision or prophylaxis of vision loss. An example of a setof dietary supplements useful in promoting healthy eyes are the ICAPS®Dietary Supplements (Alcon Laboratories, Inc., Fort Worth, Tex.).Dietary supplements are generally in the form of powders, tablets,capsules or gel-caps and comprise a variety of vitamins, minerals, andherbal or other organic constituents. Some dietary supplements areformulated with beadlets.

Beadlets contain dietary substances and are generally small spheroids ofless than about a millimeter in diameter. There are a variety offunctions and purposes of beadlets. For example, beadlets may providefor the separate containment of ingredients within the dietarysupplement to improve the stability of the entrapped ingredients.

Various beadlet compositions are known and can be obtained from a numberof food ingredient or pharmaceutical manufacturers including H. ReismanCorp. (Orange, N.J.), BASF (Mount Olive, N.J.), BioDar (Israel), andHoffinann-LaRoche (Nutley, N.J.). Particular beadlet compositions havebeen the subject of several patents including U.S. Pat. Nos. 4,254,100(Keller et al.) and 3,998,753 (Antoshkiw et al.). Numerous methods ofbeadlet manufacture have been disclosed, e.g. in U.S. Pat. Nos.4,670,247; 3;998,753 and published U.S. application No. 20030064133.

Current beadlet compositions used in dietary supplements generally arerestricted to the use of inert ingredients and excipients complementaryto a single nutritional compound. In other instances, when molecules ofthe same class are refined from a particular source, for example a majorcomponent with a minor related constituent, and both compounds produceparallel effects, such molecules may not necessarily be isolated butmixed together in a beadlet. These may be consideredpseudo-single-component beadlets, and there are examples in the marketplace, e.g., Lutrinol® and FloraGLO® beadlets, which are a combinationof lutein and zeaxanthin as formulated in Retoxil® Dietary Supplements.Examples of ingredients benefiting from beadlet confinement haveincluded natural vitamins such as Vitamins A, D, E, and K; xanthophyllssuch as lutein, zeaxanthin, canthaxanthin, and astaxanthin; andcarotenes, such as beta-carotene, lycopene, and retinol.

Recent data has suggested that the inclusion of xanthophylls and othercarotenoids in dietary supplements may provide superior dietarysupplements useful in enhancing the health of the eye. Studies haveshown the selective uptake of the carotenoids, zeaxanthin and lutein, bythe macula of the eye (Bernstein et al. 1997; Hammond et al. 1997; andHandelman et al. 1991). This earlier work revealed the presence of bothlutein and its positional isomer, [R,R]-zeaxanthin. More recently, asecond isomer of zeaxanthin has been found in the macula, thediastereomer meso-zeaxanthin, the [R,S] isomer of zeaxanthin (Bone &Landrum). These and related observations suggest both are essential forimproved ocular health and protection of the macula.

Xanthophylls are effective phytochemical antioxidants and are known tolocalize in the macula of the retina. It has been suggested that theparticular xanthophylls, zeaxanthin and its isomer lutein, may bebeneficial in improving the health of the macula and the clarity of thelens. These molecules may function in a number of ways to protect theeye from high intensity radiation or other insults. It has beensuggested that foveal proteins bind the xanthophylls, localize andconcentrate xanthophylls within the fovea. Since xanthophylls arecapable of absorbing photoexcitative radiation of short visiblewavelength, they also may shield the light-sensitive, underlying cellsof the neural retina and RPE. Such cells are responsible forhigh-definition vision and have been shown by epidemiological studies tobe adversely affected by exposure to high intensity radiation or evenchronic exposure to visible wavelength radiation. The carotenoids arebelieved to complement the activity of these cells, and also to protectthem against photochemical insult. See, e.g., Snodderly (1995) andSeddon et al. (1994).

Studies also have shown that the portion of the retina associated withxanthophyll deposition undergoes one of the highest metabolic rates inthe body (Berman 1991). The energy to sustain this metabolism is derivedfrom oxidation. While the very lipophilic xanthophylls do not appear toundergo rapid turnover characteristic of water-soluble antioxidants(Hammond et al. 1997), continuous exchange of xanthophylls occurs inresponse to both environmental challenge and tissue environment, andtheir gradual depletion without nutritional replacement may portendtissue damage (Hammond et al. 1996a; Hammond et al. 1996b; and Seddon etal. 1994). The lack of rapid turnover also implicates the role of othersynergistic antioxidants, vitamins C and E especially but also enzymaticantioxidants that are active in the redox cascade that passes theinitial oxidative excitation to lower-energy and less damaging species.

The carotenes are conjugated C₄₀ compounds that include beta carotene (aprovitamin A precursor). The carotenes are deeply colored compounds andare found throughout the plant kingdom, e.g., in leafy vegetables suchas spinach and kale, and brilliantly colored fruits such as melons andpineapple. While the carotenes are ubiquitous in the plant kingdom, theygenerally are not available biosynthetically in mammals. Since thecarotenes are essential for normal mammalian health, mammals need toingest various sources of the carotenes, e.g., fruits and vegetables.The absence of carotenoids from the diet, especially the carotenederivative, vitamin A, is known to be associated with degenerative eyediseases.

SUMMARY OF THE INVENTION

The present invention is directed to improved cobeadlet formulationsuseful for inclusion in dietary supplements. In particular, the improvedcobeadlets comprise one or more xanthophylls; one or more carotenes,retinoids or combinations thereof, one or more antioxidants; andexcipients. Preferred cobeadlets may also contain one or morebioflavonoids. The cobeadlets are particularly useful for incorporationin dietary supplements customized for improving ocular nutrition. Theirrole includes stabilization of the highly oxidizable contents tochemical reaction or physical degradation, and their purpose is toprovide concentrated more efficient carriers permitting the inclusion ofa greater number of synergistic components in the supplement dosageform.

The present invention is also directed to improved dietary supplementscomprising the improved cobeadlets. Preferred dietary supplements havebeen formulated as an aid to ocular health. The present invention isalso directed to methods of using the cobeadlets and dietary supplementsfor improving nutritional health. The methods of the present inventionare particularly directed to the enhancement of ocular health and theprophylaxis of retinal disorders, including age-related maculardegeneration.

One advantage of the cobeadlets of the present invention is that theyprovide one or more xanthophylls and one or more carotenes in a singlecobeadlet formulation. Because these molecules contain multiple,conjugated double bonds, they are highly susceptible to degradation.Consequently, antioxidants have been required in dietary supplements toprevent premature oxidation of xanthophylls and carotenes duringprocessing, manufacture, and storage. By coupling these mutuallyvulnerable components and the necessary antioxidants in one cobeadlet,the amount of stabilizing (antioxidant) component in the overall dietarysupplement can be reduced, since the stabilizing components aredistributed more proximately to the xanthophylls and carotenes, therebyconcurrently stabilizing both of these carotenoids. In addition, thecarotenes and xanthophylls, together in a single cobeadlet, may serve tostabilize each other. Since the stabilizing antioxidant components areoften in excess of the active xanthophyll and carotene component, thetotal amount of the stabilizing antioxidant and other excipientsincluding osmolality modifiers and polymers can become important,especially in a dosage form in which the presence of excess excipientdiminishes the amount of the nutritional components that can becontained in the dosage form. In other words, an excess of excipient maydisplace crucial amounts of other vitamins, minerals or other dietarysubstances in the dosage form.

Another advantage of the cobeadlets of the present invention is that thejuxtaposition of the carotenes and xanthophylls in a single cobeadlet,with or without absorption enhancing excipients, may allow forabsorption synergy and/or activity synergy, leading to enhancednutritional efficacy of the dietary supplement. Such synergy may arise,for example, when their properties—physical, chemical orphysiological—are sufficiently similar that the bioavailability orsite-specific targeting of these active ingredients may be manipulatedconcurrently using the single cobeadlet technology. The synergy alsoarises from the utility of a more efficient beadleting process; fewerand lower levels of excipients permit the addition of either more or agreater variety of total active components in the entire dosage form.

A related advantage of the coupling of these and other nutritionalcomponents into one cobeadlet is the potential for manipulating andimproving competitive absorption of these agents. For example, if thecobeadlets are also comprised of a timed-release polymer, the release ofthe nutritional components may be controlled and thus synchronized,e.g., delivering them to the upper intestine at the same time wheresolubilization by chylomicron-forming bile salts can facilitatesynchronous absorption.

Another advantage of the cobeadlets is that, as a practical matter offormulation, the amounts of xanthophyll and carotene can be manipulatedbetter as a single cobeadlet entity, as opposed to adjusting theindividual xanthophyll and carotene components of the finished dietarysupplement. In other words, the cobeadlet composition may besignificantly altered while the dietary supplement preparation using thesame size and number of cobeadlets (but now different cobeadletcomposition) would be unaffected. For example, little or no change indietary supplement preparation would be expected for a change informulations in which a 3% lutein/0% zeaxanthin/3% weight/weight (“w/w”)Vitamin A containing cobeadlet was replaced by a 0% lutein/3%zeaxanthin/3% w/w Vitamin A containing cobeadlet. And in both cases theamount of both the complementary antioxidant and other supplementaryconstituents within the cobeadlet may remain invariant. This simplifiesthe reformulation process of a complex dietary supplement (oftencontaining 30 or more components) and would be useful in view of theneed to respond to new scientific information directing modifications ofnutritional components of dietary supplements. This advantage greatlyimproves the turn-around time and reduces the cost of reformulation ofsuch dietary supplements.

Still another advantage of the cobeadlets of the present invention isthat they allow better manipulation of the appearance of the dietarysupplement. Because many carotenes and xanthophylls have multiple,conjugated double bonds, they are intensely colored (oranges to red) andhydrophobic. Thus, specialized techniques have been generally requiredto compress tablets containing such components so that the dietarysupplement form does not crumble and the components do not “bleed”within the supplement form, and to coat the cobeadlet-containingsupplement form uniformly and consistently so that no unattractivediscoloration or pitting occurs. Combining the carotenes andxanthophylls in a single cobeadlet lessens the problems of tableting andtablet coating. Thus, once having developed a dietary supplement using acoating technology capable of screening and disguising imperfectionsintroduced by the cobeadlet onto the surface of the dosage form, minorreformulations of a single complex cobeadlet, would obviate therequirement to redevelop the entire dietary supplement coating andtableting technologies.

The application of the cobeadlet technology of the present invention todietary supplements provides, and facilitates development of, enhancednutritional supplementation. Such technology may aid in increasingbioavailability of the dietary substances and also provide ease inmodifying compositions containing xanthophylls/carotenes andcomplementary antioxidants within the supplement. Such improvements arebelieved to be particularly useful in the enhancement of ocularnutrition and improved ocular health.

DETAILED DESCRIPTION PREFERRED EMBODIMENTS

According to the present invention, the elements of the composition aredirected toward scavenging free radicals and oxidants or in other waysretarding disease progression of macular degeneration. The free radicalsto which the present invention is directed primarily include superoxide.The oxidants primarily include peroxide.

As used herein, the term “dietary supplement” is meant to encompass anyform of dietary supplement, such as the tablet, caplet, gelcap, etc.

The items and doses in the present invention are consistent with thosereadily available in health food stores. The composition is preferablyin tablet or caplet form for oral administration, with the patienttaking one to four tablets or caplets taken once or twice a day. Thepresent invention, however, contemplates that the preferred total dosagecan be administered as a single dose or other multiple part dosages. Thecomposition may also be of the timed-release or delayed-release types.Further, for oral administration, the present composition may be incapsules, lacquered tablets, or unlacquered tablets, according towell-known methods. In accordance with the preferred multiple dosagesdescribed above, each tablet or caplet is preferably composedapproximately as follows:

Vitamin C

It has been known that there are high concentrations of Vitamin C bothin the normal human lens and in the aqueous humor that surrounds thelens, and that this is an antioxidant (Harris 1933). It has also beenshown in the past that generally increasing dietary Vitamin C generallyincreases the concentration of ascorbate in the aqueous humor and in thehuman lens (Ringvold 1985). It has also been known that Vitamin Cconcentrations decrease with age and, in particular, in patients whohave senile cataract (Chatterjee 1956; Purcell 1968). However, thelatter study concluded that a fall in the level of ascorbic acid is notrelated to the causation of cataract. Purcell concluded that thetherapeutic administration of Vitamin C to patients with cataractsappears irrational.

There is no known optimal daily dose of Vitamin C, although the U.S. RDAis 60 mg. However, dosages of 2.0 grams and more have frequently beentaken as a supplement for general health. Although ascorbic acid or rosehips can be used, the present composition preferably utilizes Vitamin Cin the form of sodium ascorbate because of it being easily dissolved inthe digestive system and causing relatively minimal irritation. Theconcentration is at about 200-250 mg/tablet or caplet, or a preferredtotal dosage of about 0.8-2 grams/day. In such concentrations, theVitamin C represents about 20-30% by weight of each tablet or caplet,which includes active as well as inactive ingredients described below.

Vitamin E

Vitamin E is also a well-known antioxidant, as already mentioned (seealso Mansour 1984). Vitamin E can work synergistically with Vitamin C inprotecting vital cell function from endogenous oxidants (Orten 1982).

A very common Vitamin E supplementation consists of 400 InternationalUnits per day. While studies that used more than 800 IU per day haveshown possible signs of toxicity, many common dietary supplementsavailable in supermarkets have 1000 units of Vitamin E daily (e.g.,Chaney 1986). The U.S. RDA is 30 IU. The present invention preferablyuses Vitamin E in the form of d,1-alpha tocopherol acetate, for which 1mg is equivalent to 1 IU. The preferred concentration is about 15 IU-400per tablet or caplet or a total daily dosage of 30-800 IU of Vitamin E.This represents from about 1% to preferably less than 20% by weight ofeach tablet or caplet.

Zinc

Zinc is known to be important to the health of the retina and thefunction of Vitamin A (Russell 1983; Karcioglu 1982; Leure-duPree 1982).Zinc is a cofactor in an enzyme required for maintaining thebioavailability of folate (Chandler et al. 1986), and folate isimportant for healthy DNA and protein synthesis. Zinc is one supplementpreviously used in a study which showed it to be significantly betterthan placebo in retarding macular degeneration changes (Newsome 1988).Zinc is also known to be an important cofactor for a whole multitude ofmetalloenzymes, not the least of which is superoxide dismutase, whichscavenges the potent oxidizer-superoxide. There are two types of SOD inmammalian cells. One type contains copper and zinc and is located in thecytosol and periplasmic space of the mitochondria. The other typecontains manganese and is in the matrix of the mitochondria (seegenerally U.S. Pat. No. 4,657,928). Mitochondria are the site of thehigh metabolic activity, and rapid oxidative processes in the retina.These isoforms of SOD and zinc are also implicated in cataract becauseboth superoxide dismutase activity and zinc are dramatically lower incataract patients than in noncataract patients (Ohrloff 1984; Varma1977; Swanson 1971). Zinc is also involved in enzymes related to themetabolism of vitamin A, regulating the levels of esterification. By sodoing, zinc is implicated in regulating the hepatic storage, release,and transport of retinol, and thereby its bioavailability for oculartissues (Russell 1983).

About 200 mg of zinc per day, although well-tolerated, has been shown tohave potential side effects, particularly blocking copper absorption,which results in the possibility of copper deficiency anemia (Fischer1983). High doses also have been shown to have the effect of loweringhigh-density lipoprotein, which may exacerbate atherosclerosis (Hooper1980).

The dosages of 100 mg zinc a day and 150 mg of zinc a day have beenknown in the past to be well tolerated without difficulty (Wagner 1985).The U.S. RDA is 15 mg. While other salt forms such as sulfate,picolinate, phosphate, and gluconate can be used, the present inventionpreferably provides the zinc in the form of zinc acetate, because of itbeing most readily dissolved, causing minimal irritation, and effectingmost rapid, complete (highest amount), and greatest percentageconversion into plasma zinc content, all of which are most desirableaspects. The preferred daily dosage range is from the RDA to a maximumof about 100 mg of a bioavailable form of zinc, such as zinc acetate.This maximum amount of zinc in a less bioavailable form such as zincoxide could range as high as 150 mg/day. Either form could beadministered in either a tablet or caplet.

Copper

Copper is another important cofactor for metalloenzymes, and is a secondnecessary cofactor for superoxide dismutase (Beem 1974). Copper has beenshown to decrease in individuals over 70 years of age and to bebasically zero in cataractous lenses (Swanson 1971). If copper issignificantly decreased, superoxide dismutase has been shown to havedecreased function, thereby hampering an important protective lensmechanism (Williams 1977). Copper is also protective of zinc toxicity,which blocks some of the zinc absorption and, therefore, decreasesbioavailability (Van Campen 1970).

Two to three mg of copper per day has been estimated to be safe andprovide adequate daily dietary intake (Pennington 1986). Two mg is theU.S. RDA. Some copper absorption will be blocked by the 100 mg of dailyzinc as provided above (Van Campen 1970). Therefore, the presentcomposition preferably provides about 1-5 mg/day. This amount isconsidered safe because in the typical American diet, particularly amongthe elderly, zinc and copper are often significantly below minimum dailyrequirements. In this embodiment of the present invention, copper isprovided preferably in the form of copper gluconate or an amino acidchelate and copper in such form typically represents less than about 3%by weight of each tablet or caplet for a typical BID administeredsupplement like ICaps® Lutein and Zeaxanthin Formula, and less than 1%for a typical QID administered supplement like ICaps® AREDS. Cupricoxide also has been utilized as a source of copper in supplements wherethe total available space in the dosage form is very limited, since thefraction of copper is higher in this compound.

Beta-carotene

It is well-known that Vitamin A is essential for vision. Vitamin A,retinol, is a C₂₀ alkene, which is combined as retinal in the retinawith opsin to form rhodopsin, a visual pigment. The transition of thecis form to the trans form of retinal results from excitation by light.Thus, clearly vitamin A is crucial in photoreception. Beta-carotene, apro-vitamin A carotenoid, is a lipid-soluble orange pigment that canserve as a self-regulating source of retinal. Both deficiency and excessof retinol can lead to fetal abnormalities since vitamin A is associatedwith not only vision but also growth, reproduction, cell proliferation,cell differentiation, and proper immune function.

The amount of β-carotene converted to retinol is biologically controlledand dictated by the need for retinol. The control is exerted through thecentral symmetric enzymatic cleavage of the C₄₀-carotenoid to theC₂₀-retinoid. Therefore, none of the types of vitamin A toxicity havebeen observed for β-carotene. Nonetheless, explicit β-carotene toxicityhas been surprisingly unearthed. While treatment of a β-carotenedeficiency reduced the incidence of esophageal and gastric cancers, acompromised handling of a xenobiotic was seen in connection with its usein treating lung cancer and cardiovascular disease in smokers given highdaily doses (i.e., 30 mg/day) of β-carotene. As a consequence, smokers(a high risk category for AMD) are encouraged not to increase theirsupplemented level of β-carotene above the RDA level. Thisrecommendation directly contradicts the recommendation coming from the7-year ARED Study, in which about 17-24 mg were consumed (AREDS ResearchGroup 2002).

The resolution of these conflicting recommendations, as prescribedbelow, is to provide a complete formulation, including the vitamins andminerals of a multivitamin consumed by two-thirds of those on the AREDstudy, maintaining the total carotenoids at the 15 mg, or lower,designated level. In this formulation, lutein and zeaxanthin aresubstituted for a portion of the β-carotene content, maintaining thedaily dosage of β-carotene at the RDA, 3 mg per day. The amount pertablet will be based on the number of tablets recommended for theparticular dosage form, generally two to four tablets per day.

Xanthophylls

While Xanthophylls are C₄₀ compounds, and are carotenoids, this subclassis distinguished by the presence of more polar groups. The lutein andzeaxanthin isomers have hydroxyl alcoholic groups on both iononeterminal rings, and this plays a profound role on the localization anduse of these carotenoids. Binding proteins specific to these lipids,control their localization in the eye, both their total absolute amountand their relative amounts. For example, observations in both primatesand humans (cadaver eyes, for example) have indicated that while luteinis the most abundant xanthophyll in the eyes, in the vicinity of thefovea the relative amount of zeaxanthin is greater than lutein. Thexanthophylls all serve as antioxidants, quenchers of free radicals, andabsorbers of blue light, and all of these are protective functions ofthese molecules for the underlying retina and its support tissue, theRPE. These xanthophylls are all isomers of one another; the zeaxanthinshave one more of the double bonds in the conjugated sequence, and solutein and zeaxanthin are positional isomers. And the two zeaxanthinisomers, 3,3′-[R,R] and 3,3′-[R,S] (the meso form) are diastereomers,differing at only one optical center. All three of these diols have beenobserved to be present in the macula.

Xanthophylls are typically considered to be very safe compounds, foundin edible plants and vegetables, from melons to corn to spinach andkale. Epidemiology has shown the incidence of AMD is lower for thoseindividuals consuming amounts in the higher quartiles and quintiles.GRAS status has been granted to lutein, in both the free alcohol andester forms. Lutein appears interconvertible to the meso form ofzeaxanthin, though the protein(s) responsible for the interconversionhave not yet been identified and so the precise mechanisms and means ofcontrolling them is unknown. As a consequence, some balance of thesexanthophylls in both diet and supplementation appears most prudent.

Both epidemiologic and prospective clinical studies indicate that highermacular levels of xanthophylls protect the retina from oxidative stress.Some data supports an increased deficit in the middle-aged and elderly.Epidemiologic data discerned that levels above 6 mg/day of xanthophyllswere beneficial in delaying onset of AMD. Studies of the impact of dieton bioavailability suggest serum levels of xanthophylls increase withina period of about four to eight weeks, and macular pigment levelsrespond more slowly but generally within four to six months, probablydependent on age, sex, and other health and risk factors of the subject.These data also suggest that both the rate of increase and the plateaulevels are dependent on the daily intake. The National Health andNutrition Examination Survey (NHANES) levels, that is the normal intake,is about 2 mg/day. Thus, in the methods and compositions of the presentinvention, the total daily supplementation of xanthophylls is preferablyin the range from 2 mg/day to 18 mg/day, more preferably less than about16 mg/day.

The present invention is directed to improved cobeadlet formulations,improved dietary supplement formulations comprising the improvedcobeadlets and methods of use. As used herein, “dietary supplement(s)”or the shortened form, “supplement(s),” refer to any finished, dietarysupplement dosage form containing dietary substances and suitable foringestion by a host, e.g., human or other mammal.

The cobeadlets of the present invention comprise one or morexanthophylls; one or more carotenes or retinoids or combinationsthereof; one or more antioxidants; and one or more solidifying agents.

As used herein, “xanthophylls” refer to hydroxy- and keto-oxidizedcarotenes and their derivatives, including both free alcohols andesters; “carotenes” refer to any of the 40-carbon carotenes and theirderivatives; “retinoids” refers to the 20-carbon Vitamin A (retinol) andits derivatives; and “carotenoids” refers to any of the xanthophylls,carotenes and retinoids or combinations thereof. Carotenoids may besynthetically derived or purified from natural sources. Syntheticpreparations may contain different isomers of carotenoids than thosecontained in the natural preparations. Depending on intended use,natural, synthetic or mixtures of both types of carotenoids may beincluded in the cobeadlets of the present invention.

The xanthophyll component may be obtained from various sources such asvegetables and herbal components, such as corn, leafy green vegetablesand marigolds; marine sources, such as krill; or microorganic sources,such as algae and gene-engineered bacterial or yeast sources.Xanthophylls may also be synthesized by methods known in the art and areavailable from various manufacturers. Examples of xanthophylls include,but are not limited to, lutein, zeaxanthin, astaxanthin, canthaxanthin,cryptoxanthin and related oleoresins (e.g., fatty acid mono anddi-esters of xanthophylls). The xanthophyll purity and concentration inthe various commercial sources will vary. For example, some sources mayprovide about a 1% weight/weight (“w/w”) or less of xanthophyll in oilwhile other sources, e.g., Kemin Laboratories, Inc. (Des Moines, Iowa),may provide a source in excess of 20% w/w xanthophyll in oil.Xanthophyll sources may be preparations of individual xanthophylls orcombinations thereof, and may range in concentration depending on thediluent, or in fact their absence since some preparations of powder or‘cake’ may provide a more preferable raw material. For example, axanthophyll preparation may comprise lutein as the sole xanthophyll or acombination of lutein and zeaxanthin, including combinations of thediastereomers of zeaxanthin ([R,R′], [R,S], [S,R], and [S,S]), whereinpreferred combinations include a mixture of lutein, [R,R′]-zeaxanthinand meso-zeaxanthin. Other preferred combination include a mixture of[R,R′]-zeaxanthin and meso-zeaxanthin and/or a mixture of lutein and anyone diastereomer of zeaxanthin. The inclusion of a combination ofxanthophylls in the cobeadlets, and in particular ratios, may beparticularly important when it is the intention to deliver suchcombinations to the host in ratios similar to those found in the retinabroadly, or in the macula or fovea of the eye, specifically, or in otherratios which, when injested, support the ratios in the host tissues.Xanthophylls may also be included in the cobeadlets as conjugatedderivatives, e.g., oleoresins of xanthophylls, as exemplified above.

The carotene, retinoid or combinations thereof component (hereinafterreferred to as “carotene(s)/retinoid(s)”) may be obtained from varioussources such as vegetable and herbal sources, such as corn and leafyvegetables, and fermentation product sources available from the biotechindustry. The carotenes/retinoids may also be synthesized by methodsknown in the art. Examples of carotenes include, but are not limited to,alpha-, beta-, gamnmia-, delta-, epsilon- and psi-carotene, isomersthereof. Examples or retinoids include, but are not limited to, VitaminA and Vitamin A analogs (e.g., retinoic acid). The carotene/retinoidpurity and concentration in the various commercial sources will vary.For example, some sources may provide about a 1% w/w or less ofcarotene/retinoid in oil, or as an oil suspension, or in a protected dryform, e.g., a cobeadlet.

The concentrations of the xanthophylls and carotenes/retinoids in thecobeadlets will vary, but will be in amounts useful for inclusion of thecobeadlets in dietary supplements. In general, the combinedconcentration of xanthophylls and carotenes/retinoids in the cobeadletswill be in the range of about 0.1 to 10% w/w. Preferred carotenoidconcentrations, which are generally dependent on the selection ofparticular carotenes/retinoids and xanthophylls and their relativeratios, will be about 0.5 to 7% w/w. The individual concentrations ofthe xanthophylls and the carotenes/retinoids will not necessarily be thesame. Preferred cobeadlets will have a concentration ratio from about1:10 to about 10:1 of xanthophylls:carotenes/retinoids and the mostpreferred cobeadlets will have concentration ratios from about 2:1 toabout 1:2 of xanthophylls:carotenes/retinoids.

The most preferred cobeadlets of the present invention will comprise 0.5to 7% w/w of lutein/zeaxanthin (xanthophylls) and 0.5 to 7% w/w ofβ-carotene (carotenes/retinoids).

As stated above, the cobeadlets will also contain one or moreantioxidants. The antioxidants can be hydrophobic or hydrophilic. Theantioxidants serve to inhibit the oxidative, photochemical and/orthermal degradation of the carotenoid components. Since antioxidants arealso thought to be useful in nutritional health, they may also providesome nutritional benefit to the host. In general, the antioxidants willbe natural antioxidants or agents derived therefrom. Examples of naturalantioxidants and related derivatives include, but are not limited to,vitamin E and related derivatives, such as tocotrienols, alpha-, beta-,gamma-, delta- and epsilon-tocopherol, and their derivatives, such asthe corresponding acetates, succinates; Vitamin C and relatedderivatives, e.g., ascorbyl palmitate; and natural oils, such as oil ofrosemary. Preferred cobeadlets will contain one or more hydrophobicantioxidants. The amount of antioxidant(s) contained in the cobeadletwill be an amount effective to inhibit or reduce the oxidative,photochemical and/or thermal degradation of the carotenoid components.Such an amount is referred to herein as “an effective amount of one ormore antioxidants.” In general, such an amount will range from about 0.1to 10 times the amount of the xanthophyll and carotene/retinoidcomponents and any other chemically sensitive components present, e.g.,bioflavonoids. Preferred cobeadlets, which will generally comprise about0.5-25% w/w of carotenoids alone, or including bioflavonoids, willcontain about 2 to 10% w/w of antioxidant. The most preferred cobeadletswill contain Vitamin E and, optionally, ascorbyl palmitate.

The cobeadlets will also comprise one or more solidifying, bulking andagglomerating agents (collectively referred to herein as “solidifyingagent(s)”). The solidifying agent(s) aid in transforming the carotenoidand antioxidant components into a solid suitable for granulation,tableting or blending prior to encapsulation, of the cobeadlet in thedietary supplement. The solidifying agents are particularly useful whenthe carotenoid/antioxidant components are in oils or oil suspensions.Examples of solidifying agents useful in the preparation of thecobeadlets include, but are not limited to, sucrose, glucose, fructose,starches (e.g., corn starch), syrups (e.g., corn syrup), and ionic andnonionic polymers including, but not limited to, PEGs and other polyether-like alkoxy cellulosics (HPMC), gellan, carrageenans, Eucheumagelatenae, hyaluronates, alginates, chondroitin sulfate, pectins, andproteins, (e.g., collagen or their hydrolyzed products (e.g., gelatinsor polypeptides)). Other solidifying agents known to those skilled inthe art of cobeadlet and dietary supplement preparation may also be usedin the preparation of the cobeadlets of the present invention. Theamount of solidifying agent(s) will vary, depending on the othercomponents contained in the cobeadlet, but will generally comprise themajority weight and volume of the cobeadlet.

Optionally, the cobeadlets of the present invention may also contain oneor more bioflavonoids and/or glycosidic bioflavonoids. Bioflavonoids, or“flavonoids,” are flavone- and isoflavone-like structures foundprimarily in fruits and vegetables. Bioflavonoids are commerciallyavailable or may be synthesized by methods known in the art. Examples ofbioflavonoids include, but are not limited to, quercetin, acacetin,liquritin, rutin, taxifulin, nobiletin, tangeretin, apigenin, chyrsinand kaempferol, and their derivatives, such as the correspondingmethoxy-substituted analogs. The bioflavonoids may be useful innutritional health as modulators of the rates of in vivo enzyme-mediatedreactions. The bioflavonoids may also provide antioxidant activity andmay be included in the cobeadlet for this purpose.

Other oils may be present in the cobeadlets of the present invention.The cobeadlets will typically comprise an amount of vegetable oils oroleoresins, since the separate carotene/retinoid and/or xanthophyllcomponents to be added to the cobeadlets are generally commerciallyavailable as a diluted vegetable oil or oil suspension, or as anoleoresin extract. Such an amount of oil/oleoresin typically ranges fromabout 1 to 100 times the xanthophyll or carotene content in thecobeadlet. For example, a xanthophyll extract to be included in acobeadlet may contain 20% w/w lutein, 2% w/w zeaxanthin and 78%vegetable oil/oleoresin. Other oils may also be included in thecobeadlets.

The cobeadlets of the present invention may also comprise additionalexcipients useful in preparing and finishing the cobeadlets. Suchexcipients may include timed-release polymer coating agents useful inprolonging dissolution of the cobeadlet in the digestive tract. Examplesof such polymers include, but are not limited to ionic and nonionicpolymers, such as PEGs and other poly ether-like alkoxy cellulosics(HPMC), gellan, carrageenans, Eucheuma gelatenae, starch, hyaluronates,chondroitin sulfate, pectins, and proteins, e.g., collagen. Since thexanthophyll/carotenes are highly pigmented, coating technology may beapplied to the cobeadlet in order to provide a cobeadlet of uniformcolor. Examples of color coating agents may include, but are not limitedto, polymers, colorants, sealants and surface active agents including,not limited to, fatty acids and esters, di- and triglycerides,phospholipids including mono- and di-alkyl glyceryl phosphates, nonionicagents (sugars, polysaccharides, e.g., HPMC and polysorbate 80) andionic agents.

The above-described ingredients contained in the cobeadlets may, in somecases, form microspheres within the cobeadlet. The cobeadlets may be ofvarious size and shape. In general, however, the cobeadlets will bespheroid with an approximate diameter of about 0.2 microns to 800microns.

The cobeadlets may be manufactured using a number of techniques known inthe art. For example, the cobeadlets may be prepared by blending andgranulation of the ingredients, followed by drying. The details of theseprocesses may vary according to the sequence of addition, duration andconditions for granulation, and techniques employed for drying.Preferred methods will include a low-temperature, low light-exposuredrying step capable of maintaining stability of the cobeadlet. An inert,or reduced-oxygen, atmosphere may also be employed in the manufacture ofthe cobeadlets in order to further reduce degradation of sensitivecomponents.

The present invention further provides dietary supplements containingthe cobeadlets of the invention. The cobeadlets described herein arepreferably present in the dietary supplements of the invention in anamount sufficient to provide the daily dosage (amount consumed per day)when the recommended number of dietary supplements is ingested per day.Furthermore, the dietary supplements of the invention may contain amixture of different cobeadlets, each different cobeadlet containingmultiple, but different, components described herein. That is, a portionof the cobeadlets contained in a dietary supplement as described hereinmay contain β-carotene, lutein and zeaxanthin, while another portion ofthe cobeadlets contained in the dietary supplement contains Vitamin C,Is Vitamin E, copper and zinc. It is contemplated that any combinationof components may be present in a particular cobeadlet of the invention.It is critical, however, that the dietary supplement as described hereincontain the described amounts of at least Vitamin C, Vitamin E, lutein,zeaxanthin, copper and zinc. β-carotene will also be present inpreferred dietary supplements of the invention. Each preferred componentwill typically be contained within a cobeadlet with at least one othercomponent.

The following Examples, Examples 1 and 2, illustrate preferredcobeadlets of the present invention. Example 1 illustrates the use of aconventional type of beadlet formulation and Example 2 illustrates amore recent type of beadlet in which any biohazard related to ananimal-sourced matrix component has been removed. The amount of waterpresent in the following cobeadlet examples may vary due to process andstorage conditions but will generally range from about 1-10% w/w; assuch, the other component percentage amounts may fluctuate slightly, butwill be in the same relative proportion with respect to each other.

EXAMPLE 1

Ingredient Amount % Carotenoid oleoresin 30% Hydrolyzed gelatin 33%Sucrose 13% Ascorbyl palmitate 2% Tocopherols 1% Rosemary 1% Corn starch15% Water 5%

EXAMPLE 2

Ingredient Amount % Carotenoid oleoresin 20% Sodium alginate 32%Isolated soy protein 15% Hydroxypropyl cellulose 10% Ethoxylatedglycerides 6% Rosemary or other antioxidant 5% Sucrose ester 6% Ca asthe chloride salt 5% Water 1%

The following sets of examples, Examples 2 and 3, are included todemonstrate preferred embodiments of the invention. It should beappreciated by those of skill in the art that the techniques disclosedin the examples which follow represent techniques discovered by theinventor to function well in the practice of the invention, and thus canbe considered to constitute preferred modes for its practice. However,those of skill in the art should, in light of the present disclosure,appreciate that many changes can be made in the specific embodimentswhich are disclosed and still obtain a like or similar result withoutdeparting from the spirit and scope of the invention.

The composition in Example 3 describes meaningful formulations forindividuals who are AMD patients. These compositions and dosing regimenswould be appropriate and sufficient for the daily supplement requirementof such patients.

EXAMPLE 3A

Amount Ingredient (per tab) @ QID Beta Carotene 0.75 mg Lutein 2 mgZeaxanthin 1 mg Vitamin C 125 mg Vitamin E 100 IU Copper 0.4 mg Zinc 20mg Vitamin D 100 IU Vitamin K 6.25 Vitamin B1 (thiamin) 0.375 mg VitaminB2 (riboflavin) 2.5 mg Vitamin B3 (niacin) 5 mg Vitamin B6 0.5 mgFolate/Folic Acid 100 μg Vitamin B-12 1.5 μg Biotin 7.5 μg PantothenicAcid 2.5 mg Phosphorus 27.25 mg Iodine 37.5 mg Magnesium 25 mg Selenium17.5 μg Manganese 0.5 mg Chromium 0.030 mg Molybdenum 18.75 μg Potassium20 mg Lycopene 0.075 mg DHA <25 mg Rosemary >2 mg Water 5

The following example, Example 3B, indicates that observations mayrecommend a combination of different isomers of zeaxanthin, not just allof one or the other. Alternatively in Example 3A the inference would becorrectly drawn to interpret the “zeaxanthin” to represent a ratio ofzeaxanthins, from 0 to infinite, that is all of one or the other. Thesame inference would be accurate for the Examples in the other sets.

EXAMPLE 3B

Amount Ingredient (per tab) @ QID Beta Carotene 0.75 mg Lutein 2 mg[R,R]-Zeaxanthin 0.5 mg [R,S]-Zeaxanthin 0.5 mg Vitamin C 125 mg VitaminE 100 IU Copper 0.4 mg Zinc 20 mg Vitamin D 100 IU Vitamin K 6.25 μgVitamin B1 (thiamin) 0.5 mg Vitamin B2 (riboflavin) 2.5 mg Vitamin B3(niacin) 5 mg Vitamin B6 0.5 mg Folate/Folic Acid 100 μg Vitamin B-121.5 μg Biotin 7.5 μg Pantothenic Acid 2.5 mg Phosphorus 25 mg Iodine37.5 mg Magnesium 25 mg Selenium 10 μg Manganese 0.5 mg Chromium 0.030mg Molybdenum 18.75 μg Potassium 20 mg Lycopene 0.075 mg DHA <25 mgRosemary >2 mg Water 5

The following example, Example 3C, provides higher concentrations ofcarotenoids for individuals with low serum or pigment levels.

EXAMPLE 3C

Amount Ingredient (per tab) @ QID Beta Carotene 0.75 mg Lutein 11.25 mgZeaxanthin 3.75 mg Vitamin C 125 mg Vitamin E 100 IU Copper 0.4 mg Zinc20 mg Vitamin D 100 IU Vitamin K 6.25 μg Vitamin B1 (thiamin) 0.5 mgVitamin B2 (riboflavin) 2.5 mg Vitamin B3 (niacin) 5 mg Vitamin B6 0.5mg Folate/Folic Acid 100 μg Vitamin B-12 1.5 μg Biotin 7.5 μgPantothenic Acid 2.5 mg Phosphorus 25 mg Iodine 37.5 mg Magnesium 25 mgSelenium 10 μg Manganese 0.5 mg Chromium 0.030 mg Molybdenum 18.75 μgPotassium 20 mg Lycopene 0.075 mg DHA <25 mg Rosemary >2 mg Water 5

The compositions in Examples 4 describe meaningful formulations forindividuals interested in maintaining ocular health. The composition anddosing regimen of Example 4A would be appropriate and sufficient for thedaily supplement requirement of such patients.

EXAMPLE 4 A

Amount Ingredient (per tab) @ BID Beta Carotene 1.5 mg Lutein 2 mgZeaxanthin 1 mg Vitamin C 200 mg Vitamin E 75 IU Copper 0.5 mg Zinc 20mg Vitamin D 200 IU Vitamin K 12.5 μg Vitamin B1 (thiamin) 0.751 mgVitamin B2 (riboflavin) 5.0 mg Vitamin B3 (niacin) 10 mg Vitamin B6 1 mgFolate/Folic Acid 200 μg Vitamin B-12 3.0 μg Biotin 15 μg PantothenicAcid 5 mg Phosphorus 54.5 mg Iodine 75 mg Magnesium 50 mg Selenium 35 μgManganese 1 mg Chromium 0.060 mg Molybdenum 37.5 μg Potassium 40 mgLycopene 0.150 mg DHA <50 mg Rosemary >2 mg Water TBD

The compositions in Examples 4B describe meaningful formulations forindividuals interested in maintaining ocular health yet who have a needfor higher levels of carotenoids because either their serum or pigmentlevels are low. The composition and dosing regimen of Example 4B wouldbe appropriate and sufficient for the daily supplement requirement ofsuch patients.

EXAMPLE 4B

Amount Ingredient (per tab) @ BID Beta Carotene 1.5 mg Lutein 3 mgZeaxanthin 1.5 mg Vitamin C 200 mg Vitamin E 100 IU Copper 0.5 mg Zinc20 mg Vitamin D 200 IU Vitamin K 12.5 μg Vitamin B1 (thiamin) 0.751 mgVitamin B2 (riboflavin) 5.0 mg Vitamin B3 (niacin) 10 mg Vitamin B6 1 mgFolate/Folic Acid 200 μg Vitamin B-12 3.0 μg Biotin 15 μg PantothenicAcid 5 mg Phosphorus 54.5 mg Iodine 75 mg Magnesium 50 mg Selenium 35 μgManganese 1 mg Chromium 0.060 mg Molybdenum 37.5 μg Potassium 40 mgLycopene 0.150 mg DHA <50 mg Rosemary >2 mg Water TBD

The compositions in Example 4C describe meaningful formulations forindividuals interested in maintaining ocular health, yet whose diet doesnot require the supplementation with a multivitamin. The composition anddosing regimen of Example 4C would be appropriate and sufficient for thedaily supplement requirement of such patients.

EXAMPLE 4C

Amount Ingredient (per tab) @ BID Beta Carotene 1.5 mg Lutein 2 mgZeaxanthin 1 mg Vitamin C 200 mg Vitamin E 75 IU Copper 0.5 mg Zinc 20mg Vitamin B2 (riboflavin) 5.0 mg Folate/Folic Acid 100 μg Vitamin B-123.0 μg Selenium 20 μg Manganese 5.0 mg Lycopene 0.075 mg DHA 12.5 mgRosemary >2 mg Water TBD

The composition in Example 4D describes a meaningful formulation forindividuals interested in maintaining ocular health, but have a greaterneed for the xanthophylls. This composition and dosing regimen would beappropriate and sufficient for the daily supplement requirement of suchpatients.

EXAMPLE 4D

Amount Ingredient (per tab) @ BID Beta Carotene 1.5 mg Lutein <4 mgZeaxanthin <2 mg Vitamin C <200 mg Vitamin E <200 IU Copper 0.5 mg Zinc20 mg Vitamin B2 (riboflavin) 5.0 mg Folate/Folic Acid 100 μg VitaminB-12 3.0 μg Selenium 20 μg Manganese 5.0 mg Lycopene 0.075 mg DHA 12.5mg Rosemary >2 mg Water TBD

All of the compositions and/or methods disclosed and claimed herein canbe made and executed without undue experimentation in light of thepresent disclosure. While the compositions and methods of this inventionhave been described in terms of preferred embodiments, it will beapparent to those of skill in the art that variations may be applied tothe compositions and/or methods and in the steps or in the sequence ofsteps of the method described herein without departing from the concept,spirit and scope of the invention. More specifically, it will beapparent that certain agents which are both chemically and structurallyrelated may be substituted for the agents described herein to achievesimilar results. All such substitutions and modifications apparent tothose skilled in the art are deemed to be within the spirit, scope andconcept of the invention as defined by the appended claims.

References

The following references, to the extent that they provide exemplaryprocedural or other details supplementary to those set forth herein, arespecifically incorporated herein by reference.

United States Patents and Published Applications

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Books

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1. A dietary supplement comprising cobeadlets, approximately 0.03% to0.3% copper, approximately 0.2% to 4% zinc, and Vitamin C, wherein thecobeadlets comprise Vitamin E, and active carotenoid in the form ofVitamin A, lutein and/or zeaxanthin, wherein the concentration ofVitamin C in the dietary supplement is approximately 10% to 30% byweight, the concentration of Vitamin E in the dietary supplement isapproximately 0.5% to 25% Vitamin E, and approximately 10% to 30% byweight of active carotenoid in the form of Vitamin A, lutein and/orzeaxanthin.
 2. The dietary supplement of claim 1, wherein the Vitamin Ais in the form of β-carotene.
 3. The dietary supplement of claim 1,wherein dietary supplement comprises about 1.0% to 25% by weightcobeadlets.
 4. The dietary supplement of claim 1, comprising: about 0.75mg β-carotene; about 125 mg Vitamin C; about 100 mg Vitamin E; about 0.4mg copper; about 20 mg zinc; about 2 mg lutein; and about 1 mgzeaxanthin.